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Efficacy of clinically relevant temozolomide dosing schemes in glioblastoma cancer stem cell lines

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Abstract

The effectiveness of temozolomide (TMZ) dosing schemes and the “rechallenge” of recurrent glioblastoma (GBM) with TMZ are controversial. We therefore compared the efficacy of different TMZ dosing schemes against GBM cancer stem cell (CSC) lines in vitro. In O6-methyl-guanidine-methyl-transferase (MGMT)-negative CSC lines, all schedules (1 day on/27 days off, 5 days on/23 days off, 7 days on/7 days off, 21 days on/7 days off, continuous low-dose TMZ) depleted clonogenic cells. In TMZ-resistant CSC lines, the 7 days on/7 days off scheme showed higher toxicity as compared with the other schemes. However, clinically feasible concentrations remained ineffective in highly resistant CSC lines. In addition, none of the schedules induced long-term depletion of clonogenic cells even at the highest concentrations (up to 250 μM). After sublethal TMZ treatment for 5 days, TMZ rechallenge of recovering CSC lines remained effective. Our data advocate CSC lines as in vitro model to address clinical questions. Using this model, our data suggest the effectiveness of TMZ in MGMT-negative CSC lines and support the concept of TMZ rechallenge. The 7 days on/7 days off scheme consistently showed the best activity of all schedules in TMZ-resistant CSC lines.

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Acknowledgments

This study was supported by a grant of the Bavarian Research Foundation to D.B., by the START Program (RWTH Aachen, Medical School) to D.B., the NGFNplus BTN (subproject 7A and B no. 01GS0887) to C.P.B. and P.H., and by the career award for young female scientists (RWTH Aachen, Medical School) to D.B.

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Authors and Affiliations

  1. Department of Neurology and JARA Brain, Hospital Medical School, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany

    Dagmar Beier, Jörg B. Schulz & Christoph P. Beier

  2. Department of Neurology, Medical School, University of Regensburg, Universitätsstrasse 84, 93053, Regensburg, Germany

    Dagmar Beier, Beate Schriefer, Konstantin Brawanski, Peter Hau & Christoph P. Beier

  3. Department of Neuropathology, Medical School, RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany

    Joachim Weis

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  1. Dagmar Beier
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Correspondence to Christoph P. Beier.

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Beier, D., Schriefer, B., Brawanski, K. et al. Efficacy of clinically relevant temozolomide dosing schemes in glioblastoma cancer stem cell lines. J Neurooncol 109, 45–52 (2012). https://doi.org/10.1007/s11060-012-0878-4

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  • DOI: https://doi.org/10.1007/s11060-012-0878-4

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